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Definitions

• the present invention relates to 2-thio-substituted imidazole derivatives having immunomodulating and cytokine-release-inhibiting action, to pharmaceutical compositions comprising these compounds and to their use in pharmacy.
• U.S. Pat. No. 4,585,771 discloses 4,5-diphenylimidazole derivatives which are substituted in the 2-position by a pyrrolyl, indolyl, imidazolyl or thiazolyl radical and which have antiinflammatory and antiallergic activity.
• U.S. Pat. Nos. 4,528,298 and 4,402,960 describe 4,5-di(hetero)arylimidazole derivatives which are substituted in the 2-position via a thio, sulfinyl or sulfonyl group by a phenyl, pyridyl, N-oxypyridyl, pyrimidyl, thiazolyl or thienyl radical and which have antiinflammatory and antiallergic activity.
• U.S. Pat. Nos. 4,461,770 and 4,584,310 describe 4-(5-aryl)5-(4-heteroaryl)imidazole derivatives which are substituted in the 2-position via a thio, sulfinyl or sulfonyl group by a substituted or unsubstituted aliphatic hydrocarbon and which, inter alia, have antiinflammatory action.
• DE 198 42 833 relates to 4-heteroaryl-5-phenylimidazole derivatives which are substituted in the 2-position by a phenylalkylthio group. These compounds act as antiinflammatories and inhibitors of cytokine release.
• WO 99/03837 and WO 93/14081 describe 2-substituted imidazoles which inhibit the synthesis of a number of inflammatory cytokines.
• the compounds described in WO 93/14081 have in the 2-position, attached via a sulfur atom, a phosphorus-containing substituent or an aryl or heteroaryl substituent.
• WO 91/10662 describes imidazole derivatives which inhibit the acyl-CoA: cholesterol 0-acyl transferase and binding of thromboxane TxA 2 .
• WO 95/00501 describes imidazole derivatives which can be used as cyclooxygenase inhibitors.
• the imidazole derivatives described in DE 28 23 197 A have antiinflammatory, antiallergic and immunostimulating action.
• J. Med. Chem. 1996, 39, 3927-37 describes compounds having 5-lipoxygenase- and cyclooxygenase-inhibiting action, 2-(4-methylsulfinylphenyl)-4-(4-fluorophenyl-5-(pyrid-4-yl)imidazole also having cytokine-inhibiting action.
• the present invention provides 2-thio-substituted imidazole derivatives of the formula I
• R 1 is C 1 -C 6 -alkyl which is unsubstituted or substituted by one or two hydroxyl groups or a nonaromatic heterocyclic radical, C 2 -C 6 -alkenyl, C 3 -C 6 -cycloalkyl, aryl which is unsubstituted or substituted by one or more halogen atoms or a C 1 -C 4 -alkylsulfanyl group, amino-C 1 -C 4 -alkyl, where the amino group is unsubstituted or substituted by one or two C 1 -C 4 -alkyl groups, aminoaryl, where the amino group is unsubstituted or substituted by one or two C 1 -C 4 -alkyl groups, aryl-C 1 -C 4 -alkyl or an aromatic or nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one
• the scope of the invention includes both racemates and optical isomers (enantiomers, diastereomers).
• alkyl (also in combination with other groups, such as phenylalkyl, alkylsulfonyl, etc.) embraces straight-chain and branched alkyl groups having preferably 1 to 6 or 1 to 4 carbon atoms, such as methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, sec-butyl, n-pentyl and n-hexyl.
• aryl embraces aromatic ring systems, such as phenyl or naphthyl.
• halogen represents a fluorine, chlorine, bromine or iodine atom, in particular a fluorine or chlorine atom.
• C 3 -C 6 -Cycloalkyl groups are cyclopropyl, cyclobutyl and, in particular, cyclopentyl and cyclohexyl.
• Nonaromatic heterocyclic radicals can be saturated or unsaturated. Preference is given to piperidinyl, piperazinyl, pyranyl, morpholinyl or pyrrolidinyl, where the piperidinyl radical may be substituted by 1, 2, 3 or 4 C 1 -C 4 -alkyl groups, in particular methyl groups.
• Preferred aromatic heterocyclic radicals are pyridyl, in particular 3- or 4-pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furyl, thienyl or thiazolyl.
• the heterocyclic radical, in particular the pyridyl radical may be substituted as mentioned above.
• the pyridyl radical is substituted in particular in the 2-position.
• Phenyl-C 1 -C 4 -alkyl is in particular benzyl or phenylethyl.
• radicals R 3 and R 4 are C 1 -C 4 -alkyl or a halogen-substituted phenyl and the second of the radicals R 3 and R 4 is C 1 -C 4 -alkyl or pyridyl or substituted pyridyl, with the proviso, that the two radicals are not both C 1 -C 4 -alkyl.
• R 3 is halogen-substituted, in particular 4-substituted, phenyl and R 4 is unsubstituted or substituted pyridyl, in particular 4-pyridyl or substituted 4-pyridyl.
• the radical R 3 in the formula I is 4-fluorophenyl and R 4 is 4-pyridyl or substituted pyridyl.
• R 1 is C 1 -C 6 -alkyl which is substituted by a nonaromatic heterocyclic radical, this radical preferably contains at least one nitrogen atom, and the attachment to the alkyl group is preferably via the nitrogen atom.
• R 1 is an aromatic or nonaromatic heterocyclic radical, this is preferably attached to the imidazole group via a carbon atom.
• R 1 is preferably C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, in particular cyclopropyl, or a saturated heterocyclic radical having one or two nitrogen atoms, in particular piperidinyl or 2,2,6,6-tetramethylpiperidinyl.
• the piperidinyl or 2,2,6,6-tetramethylpiperidinyl radical is attached in the 4-position to the nitrogen atom of the imidazole.
• R 2 is preferably C 1 -C 3 -alkyl (methyl, ethyl, n-propyl or i-propyl) or phenyl-C 1 -C 4 -alkyl, in particular benzyl, which may be substituted as stated above.
• R 2 is C 1 -C 3 -alkyl or benzyl which is substituted by C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkylsulfinyl or C 1 -C 4 -alkylsulfonyl, in particular in the 4-position.
• R 4 is pyridyl, in particular 4-pyridyl, which is substituted by amino, C 1 -C 4 -alkylamino or R 5 COR 6 -, where R 5 and R 6 are as defined above, R 1 is C 1 -C 3 -alkyl and R 2 is C 1 -C 3 -alkyl.
• the physiologically acceptable salts can be acid addition salts or base addition salts.
• acid addition salts inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids, such as tartaric acid, citric acid, maleic acid, fumaric acid, malic acid, mandelic acid, ascorbic acid, gluconic acid and the like, are used.
• Two process variants are available for preparing the imidazole-2-thione.
• the two variants are illustrated in an exemplary manner using compounds in which R 3 is 4-fluorophenyl and R 4 is 4-pyridyl.
• Compounds having other radicals R 3 and R 4 can be prepared in an analogous manner.
• the starting materials are converted in a condensation reaction with the aid of metallic sodium in an alcohol, for example ethanol, into 2-cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethanone (compound 1).
• the cyano group is then removed by hydrolysis, for example with hydrobromic acid, and decarboxylation, giving 2-(4-fluorophenyl)-1-(4-pyridyl)ethanone (compound 2).
• compound 2 is nitrosated in the 2-position using, for example, nitrites, such as sodium nitrite or isoamyl nitrite.
• the oxime compound of the formula (3) 2-(4-fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethane, is prepared as described in variant 1 (scheme 1, steps 1 to 3).
• the synthesis of the substituted imidazole-2-thiones is carried out according to scheme 2.
• 2-(4-Fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethane is, according to scheme 2, reacted with the selected amine of the general formula NH 2 —R 1 and formaldehyde, giving, with ring closure, a compound of the formula (6), i.e. a 1-substituted 4-(4-fluorophenyl)-5-(4-pyridyl)imidazol-2-one. This is reacted with an excess of phosphorus oxychloride, resulting in a compound of the formula (7), i.e.
• the thione compounds (5) obtained according to variant 1 or 2 are converted by substitution of the sulfur atom in the 2-position into the compounds of the formula I according to the invention where R 2 ⁇ H.
• the substitutions can be carried out in a known manner by a nucleophilic substitution reaction, as shown in an exemplary manner for some compounds in scheme 3.
• compound 5 is reacted with R 2 —X in an inert polar solvent, such as an alcohol.
• X is a readily exchangeable group, such as Hal, in particular Cl, Br, I, methylsulfonyl, tosyl etc.
• 2-Thioimidazole compounds in which the sulfur atom [lacuna] 2-position is substituted by a vinyl radical can be obtained by nucleophilic addition of compound 5 to a triple bond.
• 5 is reacted with a base, for example an alkali metal alkoxide in the corresponding alcohol, and then with an excess of the compound with the triple bond.
• the corresponding bisaryl thioethers are prepared from the 3-substituted 2-chloro-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole (compound 7 from scheme 2).
• the compounds (7) are reacted with two equivalents of the appropriate thiophenol in an aprotic solvent, such as dimethylformamide, giving compounds of the formula (12).
• the imidazolethiols which carry a C 1 -C 4 -alkyl group in the 4-position are obtained from the corresponding ⁇ -hydroxyiminoethanones (compound 17/19 in scheme 6 below), analogously to schemes 1 and 2.
• the amino group of the starting material 2-amino- ⁇ -picolin (24) is protected, for example by introduction of an acetyl group using acetic anhydride.
• the methyl group of the compound (25) is then oxidized to the carboxyl group using, for example, potassium permanganate in an aqueous medium at from 20 to 90° C.
• the amino group is again protected, for example by introducing an acetyl group using acetic anhydride.
• the resulting compound (29) is, in accordance with variant 1 or 2 (shown in scheme 8 using variant 1), converted into the thiono compound (32).
• the desired radical R 2 is introduced as described in schemes 3, 4 and 7.
• the acetyl group is initially removed hydrolytically, for example using aqueous acid, giving the amino compound (35).
• An acyl radical is introduced by acylation, in particular with the corresponding acid chloride R 5 COCl in an inert solvent, such as an ether, for example tetrahydrofuran or dioxane, or in a chlorinated hydrocarbon, for example methylene chloride or 1,2-dichloroethan, etc.
• the acylation is generally carried out in the presence of a base, for example triethylamine, in an at least equimolar amount.
• compound (35) is reacted with one or two molar equivalents of an alkyl bromide or phenylalkyl bromide in an inert solvent, such as dimethylformamide, in the presence of a base, such as sodium hydride, to give the compounds (37) or (38).
• a base such as sodium hydride
• the amide compounds (34) or (36) can be reduced with lithium aluminum hydride, for example in tetrahydrofuran, to give compound 39.
• the compounds according to the invention show immunomodulating and cytokine-release inhibiting action.
• Cytokines are proteins such as TNF- ⁇ and IL- ⁇ which play an important role in numerous inflammatory disorders.
• the compounds according to the invention are, owing to their cytokine-release-inhibiting action, suitable for treating disorders which are associated with a disturbance of the immune system.
• autoimmune disorders cancer, rheumatoid arthritis, gout, septic shock, osteoporosis, neuropathic pain, the spread of HIV, HIV dementia, viral myocarditis, insulin-dependent diabetes, periodontal disorders, restenosis, alopecia, T-cell depletion associated with HIV infections or AIDS, psoriasis, acute pancreatitis, rejection reactions of allogenic transplants, allergic pneumonia, arteriosclerosis, multiple sclerosis, cachexia, Alzheimer's disease, stroke, ictus, colitis ulcerosa, morbus Crohn, inflammatory bowel disease (IBD), ischemia, congestive heart failure, pulmonary fibrosis, hepatitis, glioblastoma, Guillain-Barre syndrome, systemic lupus erythematodes, adult respiratory distress syndrome (ARDS) and respiratory distress syndrome.
• IBD inflammatory bowel disease
• the compounds according to the invention can be administered either as individual therapeutically active compounds or as mixtures with other therapeutically active compounds.
• the compounds can be administered on their own; in general, however, they are formulated and administered in the form of pharmaceutical compositions, i.e. as mixtures of the active compounds with suitable pharmaceutical carriers or diluents.
• the compounds or compositions can be administered orally or parenterally; preferably, they are administered in oral dosage forms.
• compositions for example, can be present as tablets or capsules and may comprise customary excipients, such as binders (for example syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (for example lactose, sugar, cornstarch, calcium phosphate, sorbitol or glycerol), glidants (for example magnesium stearate, talc, polyethylene glycol or silica), disintegrants (for example starch) or wetting agents (for example sodium lauryl sulfate).
• binders for example syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone
• fillers for example lactose, sugar, cornstarch, calcium phosphate, sorbitol or glycerol
• glidants for example magnesium stearate, talc, polyethylene glycol or silica
• disintegrants for example starch
• Liquid oral preparations can assume the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or sprays and the like. They can also be present as a dry powder which is reconstituted using water or another suitable carrier. Such liquid preparations may comprise customary additives, for example suspending agents, flavors, diluents or emulsifiers. For parenteral administration, it is possible to use solutions or suspensions with customary pharmaceutical carriers.
• the compounds or compositions according to the invention can be administered to mammals (man or animal) in a dose of from about 0.5 mg to 100 mg per kg of body weight per day. They may be administered in one individual dose or in a plurality of doses.
• the activity spectrum of the compounds as inhibitors of cytokine release was examined using the test systems below, as described by C. Donat and S. Laufer in Arch. Pharm. Pharm. Med. Chem. 333, Suppl. 1, 1-40, 2000.
• test substance is added to samples of human potassium-EDTA whole blood (of 400 ⁇ l each) and the samples are preincubated in a CO 2 incubator (5% CO 2 ; 95% moisture-saturated air) at 37° C. for 15 min.
• the samples are then stimulated with 1 ⁇ g/ml of LPS ( E.coli 026:B6) at 37° C. in a CO 2 incubator (5% CO 2 ; 95% moisture-saturated air) for 4 hours.
• LPS E.coli 026:B6
• the reaction is stopped by placing the samples on ice, adding DPBS buffer and then centrifuging at 1000*g for 15 min.
• the amount of IL-1 ⁇ and TNF ⁇ in the plasma supernatant is then determined by ELISA.
• PBMCs mononuclear cells from human potassium-EDTA whole blood, diluted 1:3, are isolated by density gradient centrifugation (Histopaque®-1.077). The cells are washed twice with DPBS buffer, resuspended in macrophage SFM medium and adjusted to a cell count of 1*10 6 cells/ml.
• the resulting PBMCs suspension (samples of in each case 390 ⁇ l) and the test substance are preincubated at 37° C. in a CO 2 incubator (5% CO 2 ; 95% moisture-saturated air) for 15 min.
• the samples are then stimulated with in each case 1 ⁇ l/ml of LPS ( E.coli 026:B6) at 37° C. in a CO 2 incubator (5% CO 2 ; 95% moisture-saturated air) for 4 hours.
• the reaction is stopped by placing the samples on ice, adding DPBS buffer and then centrifuging at 15 880*g for 12 min.
• the amount of IL-1 ⁇ and TNF ⁇ in the plasma supernatant is then determined by ELISA.
• 2-(4-fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethanone was prepared as described in example 1, steps (a) to (c).
• 4.0 g of the iminoethanone were then, together with the equimolar amount of ethylamine and the equimolar amount of formaldehyde (36% strength aqueous solution), heated under reflux for 4 h.
• the reaction mixture was neutralized using aqueous ammonia and extracted three times with CH 2 Cl 2 .
• the organic phases were combined and dried over Na 2 SO 4 .
• the drying agent was filtered off and the solvent was removed using a rotary evaporator.
• the slightly oily residue was solidified by addition of diethyl ether.
• the precipitate was filtered off and dried under reduced pressure. The yield was 63%.
• step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri-n-propylhexahydro-1,3,5-triazine.
• the yield was in the range of 60-91%.
• the yield was in the range of 32-72%.
• step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tricyclopropylhexahydro-1,3,5-triazine.
• step d) the 2-(4-fluoro-phenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri(2-dimethylaminoethyl)hexahydro-1,3,5-triazine.
• step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethanone was reacted with twice the molar amount of 2,2,6,6-tetramethyl-4-methyleneaminopiperidine.
• step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethanone was [lacuna] with twice the equivalent amount of 1,3,5-tri(3-dimethylaminopropyl)hexahydro-1,3,5-triazine.
• step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri(N-morpholinopropyl)hexahydro-1,3,5-triazine.
• step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri(4-methylsulfanylphenyl)hexahydro-1,3,5-triazine.
• step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri(N-morpholinoethylhexahydro-1,3,5-triazine.
• step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri(3-hydroxypropylhexahydro-1,3,5-triazine.
• step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethanone was reacted with twice the molar amount of 1-benzyl-4-methyleneaminopiperidine.
• step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)- ⁇ -hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri(prop-2-en-1-yl)hexahydro-1,3,5-triazine.
• the title compound was prepared analogously to the process of example 20. 1,3,5-tri-n-propylhexahydro-1,3,5-triazine was used for cyclizing the imidazole compound.
• IR: 1/ ⁇ (cm ⁇ 1 ) 2929, 1601, 1511, 1221, 849, 829, 816
• the title compound was prepared analogously to the process of example 20. 1,3,5-tricyclopropylhexahydro-1,3,5-triazine was used for cyclizing the imidazole compound.
• IR: 1/ ⁇ (cm ⁇ 1 ) 2852, 1600, 1509, 1215, 1114, 871, 841, 813
• the title compound was prepared analogously to the process of example 20. 2,2,6,6-tetramethyl-4-methylenaminopiperidine was used for cyclizing the imidazole compound.
• IR: 1/ ⁇ (cm ⁇ 1 ) 2968, 1600, 1509, 1343, 1229, 1033, 835, 813
• the title compound was prepared analogously to the process of example 20.
• 1-benzyl-4-methylenaminopiperidine was used for cyclizing the imidazole compound.
• IR: 1/ ⁇ (cm ⁇ 1 ) 2972, 1602, 1509, 1343, 1222, 1092, 844, 828, 816, 743, 698
• the title compound was prepared by the process of example 27, with n-propylamine being in step (a) and 4-methylthiobenzyl chloride being used in step (b) for the benzylation.
• step (b) 4-methylsulfinyl-benzyl chloride was used for the benzylation.
• step (b) 4-methylsulfonylbenzyl chloride was used for the benzylation.
• the title compound was prepared by the process of example 27, where isopropylamine was used in step (a) and 4-chlorobenzyl chloride was used in step (b) for the benzylation.
• the title compound was prepared by the process from example 27, where isopropylamine was used in step (a) and 4-methylsulfonylbenzyl chloride was used in step (b) for the benzylation.
• the title compound was prepared by the process of example 28, where 1,3,5-tricyclopropylhexahydro-1,3,5-triazine was used in step (a) and 1-phenylprop-1-ynyl chloride was used in step (b) for the benzylation.
• step (b) 1-(4-chloro-phenyl)prop-1-enyl chloride was used for the benzylation.
• step (b) 1-phenylprop-1-enyl chloride was used for the benzylation.
• the title compound was prepared by the process of example 27 where cyclo-hexylamine was used in step (a) and 4-methylsulfonylbenzyl chloride was used in step (b) for the benzylation.
• step (a) was aniline.
• step (a) was benzylamine.
• the title compound was prepared by the process of example 27, where N-morpholinoethylamine was used in step (a) and benzyl chloride was used in step (b) for the benzylation.
• Example 28 was repeated, except that the added imine compound in step (a) was 1,3,5-tri(3-N-morpholinopropyl)hexahydro-1,3,5-triazine.
• the title compound was prepared by the process of example 28, where 1,3,5-tri(3-N-morpholinopropyl)hexahydro-1,3,5-triazine was used in step (a) and 4-methyl-sulfonylbenzyl chloride was used in step (b) for the benzylation.
• the title compound was prepared by the process of example 28, where 1,3,5-tri(3-N-morpholinopropyl)hexahydro-1,3,5-triazine was used in step (a) and 4-methylsulfinyl-benzyl chloride was used in step (b) for the benzylation.
• IR: 1/ ⁇ (cm ⁇ 1 ) 2956, 1601, 1509, 1406, 1220, 1115, 1047, 837, 815
• the title compound was prepared by the process of example 28, where 2,2,6,6-tetra-methyl-4-methylenaminopiperidine was used in step (a) and benzyl chloride was used in step (b) for the benzylation.
• step (b) 4-chlorothiophenol was used.
• step (b) 4-methylsulfanylthiophenol was used.
• step (b) was N-methylene-(N-morpholino)ethanamine.
• compound (32) Under protective gas, compound (32) is suspended in abs. ethanol, and an equimolar amount of methyl iodide is added. A spatula tip of Na 2 CO 3 is added and the reaction mixture is refluxed until the starting material has been completely converted. After cooling, the inorganic salts are filtered off and the solvent is removed using a rotary evaporator. The crude product (33) is purified by column chromatography.
• the compound of example 66 is dissolved in abs. tetrahydrofuran (THF), and 1.2 times the amount of triethylamine is added.
• THF abs. tetrahydrofuran
• the reaction mixture is cooled in an ice-bath. With stirring, 1.2 times the amount of the acid chloride is added dropwise, and stirring is continued until no more starting material is present.
• the reaction mixture is filtered and the filtrate is concentrated to dryness. Purification of the crude product is carried out by column chromatography.
• Example R 1 R 2 77 cyclo-C 6 H 11 CH 3 78 —(CH 2 ) 2 —N(CH 3 ) 2 CH 3 79 —(CH 2 ) 3 —OH CH 3 80 —(CH 2 ) 3 —OCH 3 CH 3 81 CH 3 —(CH 2 ) 2 S CH 3 82 CH 3 —(CH 2 ) 2 SO CH 3 83 cyclo-C 6 H 11 CH 2 -Ph-4-SO CH 3 84 cyclo-C 6 H 11 CH 2 -Ph-4-SCH 3

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